4-hydroxy-4-phenylpiperidines



United States Patent 01 ice W jf f 311i 3 455 935 {eduction and subsequent acylation, as shown in the folowin reacti 4-HYDROXY-4-PHENYLPIPERIDINES g on sequence Otis Earl Fancher and Shin Hayao, Elkhart, Ind., 215- Br OH signors to Miles Laboratories, Inc., Elkhart, Ind., a l 1 corporation of Indiana 5 R C a HN No Drawing. Continuation of application Ser. No. 300,086, Aug. 5, 1963. This application June 12, 1967, Ser. No. 645,863

Int. Cl. C07d 29/20 H-l US. Cl. 260-494 2 Claims 10 0 OH RJ-NH--C HN ABSTRACT OF THE DISCLOSURE Compounds of the formula: l

H OH WC\ R -NH-oH=- JH-N I 11 Q o a l (RZC O)20 where R is phenyl or phenylalkyl and where R is either R2 -orrcH,- -cH,cH- 4 0 (g 1 0H CH3 H3 R NoH,-En-N and pharmaceutrcally acceptable add1t1on salts thereof are a described. The compounds have utility as analgetic agents.

An alternative procedure where the isomeric propylene moiety is desired involves the following reaction scheme:

This invention relates to derivatives of 4-hydroxy-4- phenylpiperidine. In one of its more particular aspects, 9 H this invention relates to compounds containing the 4-hydroXy-4-PhenylPiP ridyl moiety which also contain amide CE3 CH C C1+ i Q urethane groups.

Th compounds of this invention correspond to the structural formula l Br 0 OH I wherein R may be aryl or aralkyl; R may be lower alkyl, Iii-OH T RLNHCH(LJ N\ lower alkoxy, cycloalkyl or heterocyclic and R is an CH1 Q alkylene radical.

In a preferred subgroup of compounds, R is phenyl l or phenalkyl; R is lower alkyl, lower alkoxy, cyclohexyl or furyl and R is a lower alkylene radical. OH Of particular interest are those compounds which 1 R is a branched chain propylene rad1cal, that 1s, I

1' H3 0 6 lave o),o 0

R2 The latter compounds form an especially preferred sub- (15: OH group of the compounds of this invention.

These compounds are generally furnished in the form R N E Gib-N of their water-soluble salts such as their hydrochlorides, EB oxalates, maleates, cyclohexylsulfamates or the like. They may also be provided as quaternary salts such as the methiodide if desired. The compounds of this invention are useful as analgetic The compounds of this invention may be readily preagents. pared by alkylation of 4-hydroxy-4-phenylpiperidine with This invention will be better understood by reference the appropriately substituted alkyl halide. Generally, their to the following examples which, however, are included preparation involves a series of steps including alkylation, merely for purposes of illustration.

3 EXAMPLE 1 a- (4-hyd roxy-4-phenyll-piperidyl propion anilide A. A solution of 4-hydroxy-4-phenylpiperidine (21.6 g., 0.122 mole and a-bromopropionanilide (27.9 g., 0.122 mole) in 250 ml. of 2-propanol in presence of 14.4 g. (0.124 mole of anhydrous sodium carbonate was refluxed for 16 hours with vigorous stirring. It was filtered while hot and the filtrate was concentrated in vacuo to give a solid mass which was once recrystallized from aqueous methanol to give a colorless solid of M.P. 133-134, yield 34.3 g. The filtrate was diluted with water to give a pale yellow solid of M.P. l33134, yield 2.6 g. The total yield was 36.9 g. (93.2%),

# 2.78 (OH), 2.90 (O-H), 3.02 (NH), 5.94

(am ide o=o), 5.56,. (amide II) Analysis.--Calcd. for C H N O N, 8.64. Found: N, 8.68.

l-anilino-Z-(4-hydroxy-4-phenyl-l-piperidyl)propane max. (N-H), 8.59;: (CO stretch. test. alcohol) Analysis.-Calcd. for C H N O: N (basic), 4.52. Found: N (basic), 4.51 (titration) N- [2-methyl-2-(4-hydroxy-4-phenyl-l-piperidyl ethyl] propionanilide C. The above amine (30.0 g.) was dissolved in 50 ml. of benzene and propionic anhydride ml.) was added. The solution was refluxed for an hour and the solvent was removed in vacuo. The residue was dissolved in ether, washed with sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solution was treated with 8.7 g. (0.097 mole) of anhydrous oxalic acid to give a light tan sticky gum which gradually solidified on scratching. The solid was collected on a filter, washed with ether and dried in air, yield 43.9 g. It was once recrystallized from methanol ether to give a solvated solid which was collected and dried in vacuo, yield 31.7 g., M.P. 103- 105 (dec.). The free base:

x 1.475, o-u no NH at 1.55,.

max-

Analysis. Calcd. for C23H30N202.C2H204: N, 6.14. Found: N, 6.07.

- EXAMPLE 2 4-hydroxy-4-phenyl-1- a-anilino pro pionyl )piperidine A. A toluene solution of a-bromopropionyl chloride (68.6 g., 0.4 mole) was added slowly to an ice cold, stirred suspension of 4-hydroxy-4-phenylpiperidine (70.8 g., 0.4 mole) in 750 ml. of toluene and 130 ml. of 20% sodium hydroxide and the stirring was continued overnight. The layers were separated and the dried toluene layer was concentrated in vacuo to half its volume. This concentrate and aniline (74.4 g., 0.8 mole) were heated under reflux with stirring for 16 hours. The solvent was removed in vacuo to leave a solid mixture of amide and aniline hydrobromide. This solid was suspended in water and let stand overnight. The solid amide was then collected washed with water and dried. The solid was triturated in ether and again collected and dried, yield 112.9 g. (87% M.P. 147.5-148.5.

Analysis.Calcd. for C H N O N, 8.64. Found: N, 8.65.

4 2-anilino-1-(4-hydroxy-4-phenyl-l-piperidyl) propane B. A tetrahydrofuran solution of the above amide (112.9 g., 0.348 mole) was added slowly to a stirred suspension of lithium aluminum hydride (19.8 g., 0.522 mole) in 400 ml. of tetrahydrofuran and the mixture was heated under reflux for 8 hours. The excess lithium aluminum hydride was decomposed by slowly adding a solution of 20 ml. of water in ml. of tetrahydrofuran, followed by 20 ml. of 20% sodium hydroxide and 60 ml. of water. The mixture was filtered and the filtrate was concentrated in vacuo to a viscous liquid. An LR. gave an amide carbonyl band at 6.10 to indicate incomplete reduction. The reduction was repeated and the excess lithium aluminum hydride was decomposed in the same manner. The mixture was filtered and the filtrate was concentrated in vacuo and distilled, using a short path column, B.P. -210 (0.20-0.30 mm.), yield 39.5 g. (36.6%

Analysis.-Calcd. for C H N Oz N, 9.03. Found: N, 9.04.

N- 1-methyl-2- 4-hydroxy-4-phenyl-l-piperidyl) ethyl] propionanilide oxalate anhydride (39 g., 0.3 mole) and 250 ml. of benzene was heated under reflux for 3 hours. The solvent was removed in vacuo and the dark oil was dissolved in chloroform and washed with dilute sodium hydroxide solution. The chloroform layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The concentrate of free base was dissolved in ether and an ether solution of oxalic acid (18 g., 0.2 mole) was added with cooling to form a sticky solid. The solvent was decanted and fresh ether was added. On cooling, the salt slowly solidified. The solid was collected and twice recrystallized from a methanol-ether solution, yield 41 g. (72%), M.P. 165.5-l67.0 (dec.).

Analysis.Calcd. for C H N O .C H O N, 6.14; N (basic), 3.07. Found: N, 6.19; N (basic), 3.10.

EXAMPLE 3 1- (2-propionanilido propyl -1-methyl-4-hydroxy- 4-phenylpiperidinium iodide A solution of N-[1-methyl-2-(4-hydroxy-4-phenyl-1- piperidyl)ethyl] aniline (18.2 g., 0.06 mole), propionic anhydride (13 g., 0.1 mole) and 200 ml. of benzene was heated under reflux for 3 hours. The solvent was removed in vacuo and the concentrate was dissolved in chloroform, washed with ammonium hydroxide and the solvent was again removed in vacuo. The concentrate was dissolved in acetone and 15 g. (0.105 mole) of iodomethane was added. The solution was heated on the steam bath for 15 minutes. The solvent was removed in vacuo and the oil failed to crystallize from several solvent combinations. The solvent was removed in vacuo and ether was added with cooling to slowly solidify the salt. The salt was collected and again triturated in ether. The solid was collected and dried in vacuo over refluxing acetone. The salt softened and decomposed over a range of 72-84", yield 13.0 g. (42.7%).

Analysis.Calcd. for C H IN O C, 56.7; H, 6.50; N, 5.51. Found: C, 56.3; H, 6.64; N, 5.54.

EXAMPLE 4 N [2- (4-hydroxy-4-phenyl-l-piperidyl) propyl] benzylamine A. A mixture of N-benzyl'a-bromopropionamide (48.4 g., 0.2 mole), 4-hydroxy-4-phenylpiperidine (35.4 g., 0.2 mole), sodium carbonate (23.4' g., 0.22 mole) and 400 ml. of 2-propanol was heated under reflux with stirring for 18 hours. The mixture was cooled, filtered and the filtrate was concentrated in vacuo to a viscous amide.

tilled, B.P. 195-205 (0.075 mm.), yield 20 g. (31%).

Analysis.-Calcd. for C H N O: N (basic), 8.65. Found: N (basic), 8.03.

N-benzyl-N- [2- (4-hydroxy-4-phenyl- 1 -piperidyl propyl]propionamide oxalate B. A mixture of N- [2-(4-hydroxy-4-phenyl-l-piperidyl)propyl]benzylamine (20 g., 0.062 mole) propionic anhydride (26 g., 0.2 mole) and 250 ml. of dry benzene was heated under reflux for 2 hours. The solvent was removed in vacuo and the cooled residue was made basic with dilute sodium hydroxide solution and extracted with ether. The extracts were dried (MgSO and concentrated in vacuo. A crystalline free base could not be prepared.

An ether solution of oxalic acid (12 g., 0.13 mole) was added to an ether solution of the free base. The solvent was decanted from the sticky salt that formed and fresh ether was added to form a solid after standing for several days. The solid was recrystallized from a 2-propanolether solution, yield 7.9 g. (24.5%), M.P. 142-144 (dec.).

AHHZYSLSr-CHICCI. for C24H32N2O2'C2H2O4I N, 5.96. Found: N, 6.07.

EXAMPLE 5 N-carbethoxy-N- l-methyl-2- (4-hydroxy-4-phenyll-piperidyl) ethyl] aniline sulfamate A chloroform solution of ethyl chloroformate (8.8 g., 0.08 mole) was added dropwise to a solution of N-[lmethyl 2 (4 hydroxy 4 phenyl 1 piperidyl)- ethyl] aniline (25 g., 0.08 mole) in 200 ml. of chloroform and the solution was stirred overnight. The solution, containing a small amount of solid was made basic with ammonium hydroxide and the chloroform layer was sep arated and concentrated in vacuo to an oil. This free base was dissolved in hot methanol and an aqueous methanol suspension of sulfamic acid (7.8 g., 0.08 mole) was added and the solution that formed on additional heating was filtered and diluted with ether to form a solid. The solid was collected and recrystallized from a methanol-ether solution, M.P. l85l85.5 (dec.), yield 11.3 g. (29.3%).

Analysis.--Calcd. for C H N O -NH SO H: N, 8.76; N (basic), 2.92. Found: N, 8.65; N (basic), 2.99.

EXAMPLE 6 N- 1-methyl-2-(4-l1ydroxy-4-phenyl-l-piperidyl) ethyl]-B-phenethyl-amine A. A benzene solution of a-bromopropionyl chloride (60 g., 0.34 mole) was added slowly to an ice-cold, stirred solution of 4-hydroxy-4-phenylpiperidine (62 g., 0.35 mole) in 300 ml. of benzene and 110 ml. of 20% NaOH and the mixture was stirred in the cold for an additional hour. The benzene layer was collected and concentrated to half its volume. This solution, ,B-phenethylamine (85 g., 0.7 mole) and 250 ml. of toluene were heated under reflux with stirring for 18 hours. The mixture was filtered and the filtrate was concentrated in vacuo to an oil. This oil in 250 ml. of THF was slowly added to a stirred suspension of LiAlH, (20 g., 0.512 mole) in 250 ml. of THF and the mixture was heated under reflux for 20 hours. The excess LiAlH, was decomposed by slowly adding a solution of 20 ml. of water and 80 ml. of THF, followed by 20 ml. of 20% sodium hydroxide solution and 60 ml. of water. The mixture was filtered and the filtrate was concentrated in vacuo to a solid. This solid was recrystallized from a DMF-methanol-water solution. M.P. 120.5-121.5, yield 75.4 g. (64%).

Analysis.--Calcd. for C H N N (basic), 8.28. Found: N (basic), 8.33.

N-fi-phenethyl-N- 1-methyl-2-(4-hydroxy-4-phenyll-piperidyl ethyl] propionamide hydrochloride B. A mixture of N-[1-methyl-2-(4-hydroxy-4-phenyl-lpiperidyl)ethyl]-/8-phenethylamine (25 g., 0.074 mole), propionic anhydride (26 g., 0.2 mole) and 200 ml. of benzone was heated under reflux for 3 hours. The solvent was removed in vacuo and concentrate was dissolved in chloroform, made basic with ammonium hydroxide and the chloroform layer was collected and concentrated in vacuo. This concentrate was dissolved in methanol and 25 ml. of 2-propanol, saturated with dry HCl, was added. This solution was filtered and the filtrate was diluted with ether to form a white solid. The solid was collected, washed with ether and dried. M.P. 18919l (dec.), yield 16.8 g. (52.8%).

AVZIZIYSiS.-C31Cd. for C25H34N202'HC1: N, N (basic), 3.25. Found: N, 6.62; N (basic), 3.31.

EXAMPLE 7 N-Z-furoyl-N- 1-methy1-2- (4-hydroxy-4-phenyll-pip eridyl) ethyl] aniline hydrochloride A chloroform solution of 2-furoylchloride (10.5 g., 0.0806 mole) was added dropwise to a solution of N-[lmethyl 2 (4 hydroxy 4 phenyl 1 piperidyl)ethyl] aniline (25 g., 0.0806 mole) in 200 ml. of chloroform and the mixture was stirred for an additional hour. Only a small amount of solid was formed, so the solution was made basic with ammonium hydroxide and the chloroform layer was concentrated in vacuo to an oil. The free base was dissolved in ethanol and a 2-propanol solution, containing 8 g. of dry HCl, was added and the solution was diluted with ether and cooled. This solid was collected by filtration and was the dihydrochloride of the starting material. A crystalline solid separated in the filtrate. It was collected and dried, M.P. 200202 (dec.), yield 4 g.

Analysis.Calcd. for C H N O -HCl: N, 6.36; N (basic), 3.18. Found: N, 6.28; N (basic), 3.12.

EXAMPLE 8 N-[ 1-rnethyl-2- 4-hydroxy-4-phenyl- 1 -piperidyl) ethyl] cyclohexanecarboxanilide A chloroform solution of cyclohexanecarbonyl chloride (12 g., 0.08 mole) was slowly added to a stirred solution of N- 1-methy1-2- 4-hydroxy-4-phenyl-l-piperidyl] aniline (18.6 g., 0.06 mole) in m1. of chloroform and the solution was heated under reflux for 2 hours. The solvent was removed in vacuo and the concentrate was dissolved in a methanol-ether solution and an ether solution of oxalic acid (9 g., 0.1 mole) was added. The salt oiled out, but slowly solidified on cooling. The solid was recrystallized once from an ethanol-ether solution and once from ethanol, yield 4.2 g. (13.7%), M.P. l65.5167.0 (dec.).

Analysis.Calcd. for C21H35N202'C2H204: N, N (basic), 2.75. Found: N, 5.41, N (basic), 2.63.

In summary, this invention provides a series of novel therapeutic compounds of the 4-hydroxy-4-phenyl piperidine series which have the above described formula. These compounds are potent narcotic-like analgetic agents.

What is claimed is:

1. A compound selected from the group consisting of compounds of the formula in which R is a member selected from the group consist- References Cite ing of phenyl and phenylalkyl, R is a member selected UNITED STATES PATENTS f tin f mm the gmup wnsls g 2,960,507 11/1960 Stern and Watt zen-294.7 CH H 2,973,363 2/1961 Janssen 260293.4 and 5 3,290,317 12/1966 Carabateas 260--293.4

H3 HENRY R. JILES, Primary Examiner and therapeutically acceptable salts thereof. THOMAS TODOL Assistant Examiner 2. A compound of claim 1 which is N-Z-furoyl-N-[l- 10 US. Cl. X.R.

methyl-2- (4-hydroxy-4-phenyll-pip eridyl) ethyl] aniline. 260294.7, 999

PEI-1050 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 455, 935

Dated July 15, 1969 Inven or) Otis Earl Fancher and Shin Hayao It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, Lines 45-50,

Column 6, Line 49 (SEAL) Attest:

Edward M. Fletcher, I r.

Attesting Officer SIGNED AN'U SEALED DEC 2-1969 comissioner of Patents 

